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<p>In vivo CRISPR gene editing holds enormous potential for various diseases. Ideally, CRISPR delivery should be cell type-specific and time-restricted for optimal efficacy and safety, but customizable methods are lacking. Here we develop a cell-tropism programmable CRISPR–Cas9 ribonucleoprotein delivery system (RIDE) based on virus-like particles. The efficiency of RIDE was comparable to that of adeno-associated virus and lentiviral vectors and higher than lipid nanoparticles. RIDE could be readily reprogrammed to target dendritic cells, T cells and neurons, and significantly ameliorated the disease symptoms in both ocular neovascular and Huntington’s disease models via cell-specific gene editing. In addition, RIDE could efficiently edit the huntingtin gene in patients’ induced pluripotent stem cell-derived neurons and was tolerated in non-human primates. This study is expected to facilitate the development of in vivo CRISPR therapeutics.</p>

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Customizable virus-like particles deliver CRISPR–Cas9 ribonucleoprotein for effective ocular neovascular and Huntington’s disease gene therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月10日

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  • Sikai Ling,
  • Xue Zhang,
  • Yao Dai,
  • Zhuofan Jiang,
  • Xujiao Zhou,
  • Sicong Lu,
  • Xiaoqing Qian,
  • Jianping Liu,
  • Niklas Selfjord,
  • Tugce Munise Satir,
  • Anders Lundin,
  • Julia Liz Touza,
  • Mike Firth,
  • Natalie Van Zuydam,
  • Bilada Bilican,
  • Pinar Akcakaya,
  • Jiaxu Hong,
  • Yujia Cai

摘要

In vivo CRISPR gene editing holds enormous potential for various diseases. Ideally, CRISPR delivery should be cell type-specific and time-restricted for optimal efficacy and safety, but customizable methods are lacking. Here we develop a cell-tropism programmable CRISPR–Cas9 ribonucleoprotein delivery system (RIDE) based on virus-like particles. The efficiency of RIDE was comparable to that of adeno-associated virus and lentiviral vectors and higher than lipid nanoparticles. RIDE could be readily reprogrammed to target dendritic cells, T cells and neurons, and significantly ameliorated the disease symptoms in both ocular neovascular and Huntington’s disease models via cell-specific gene editing. In addition, RIDE could efficiently edit the huntingtin gene in patients’ induced pluripotent stem cell-derived neurons and was tolerated in non-human primates. This study is expected to facilitate the development of in vivo CRISPR therapeutics.